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Published OnlineFirst January 14, 2015; DOI: 10.1158/0008-5472.CAN-14-2748
Cancer
Research
Review
Th9 Cells: A Novel CD4 T-cell Subset in the
Immune War against Cancer
de
rique Ve
gran1,2, Lionel Apetoh1,2,3, and François Ghiringhelli1,2,3
Fre
Abstract
CD4 T cells are key components of the immune system that
shape the anticancer immune response in animal models and
in humans. The biology of CD4 T cells is complex because na€ve
T cells can differentiate into various subpopulations with
various functions. Recently, a new population called Th9 cells
was described. These cells are characterized by their ability to
produce IL9 and IL21. They were first described in the context of
parasite infections and allergic processes. However, some
reports described their presence in the tumor bed in mice and
humans. Their high secretion of IL9 and IL21 in the tumor bed
contributes to their anticancer functions. Indeed, these cytokines trigger the activation of dendritic cells, mast cells, natural
killer cells, and CD8 T cells to mount an antitumor immune
response, thus explaining the remarkable ability of Th9 cells to
control tumor growth. This review summarizes the latest
advances in the Th9 field in cancer and focuses on their
potential role as new tool for cell therapy. Cancer Res; 75(3);
The Role of CD4 T-cell Polarization in
Cancer
tumors by follicular helper T cells seems to be associated with a
coordinated antitumoral immune response and a better clinical
outcome (5). The role of Th17 cells in cancer remains a matter of
debate. IL17 could promote neoangiogenesis and the expression
of prosurvival genes in cancer cells (6). In addition, ectonucleotidase-expressing Th17 cells compromise anticancer immunity
through adenosine (7), whereas adoptively transferred Th17 cells
demonstrated dramatic anticancer functions in vivo notably via
their ability to differentiate into IFNg-producing cells (8).
In 2008, IL9-producing CD4 T helper cells (Th9) were
identified as a new subset of CD4 T helper cells with proinflammatory functions (9, 10). Th9 cells arise from reprogrammed Th2 cells upon stimulation with TGFb (9, 10). Mouse
and human Th9 cells secrete IL9 and IL21 and were initially
proposed to contribute to the development of autoimmune
and allergic diseases (11, 12). We and others, however, recently
found that Th9 cells also featured potent anticancer properties
(13–15). In this review, we discuss the potential of using Th9
cells for anticancer immunotherapy.
Since the seminal observations of Dunn and colleagues (1) on
cancer immunosurveillance, the role of the adaptive immune
system in the development of cancer or tumor growth is clearly
established. CD4 helper T cells are key elements of the adaptive
immune response, and are known to differentiate from a na€ve
population into helper memory populations after stimulation by
T-cell receptor (TCR) triggering by the cognate antigen and a
particular cocktail of cytokines. The original classification of CD4
T lymphocytes by Mosmann and Colleagues (2) described two
populations of effector CD4 T cells called Th1 and Th2 subsets. Th1
are IFNg-producing cells and were known as the classical antitumor cells because of the capacity of IFNg to activate the killer
functions of macrophages, natural killer (NK) cells, and CD8 CTLs.
Th2 cells are characterized by their production of IL4, and play a
central role in the development of asthma and atopic dermatitis.
The role of Th2 cells in cancer is mainly deleterious as IL4 directly
favors tumor growth. In addition, Th2 cells could induce M2
polarization of tumor-infiltrating macrophages, which drive tumor
immune tolerance and neoangiogenesis (3). CD4 T cells are now
known to differentiate into additional new effector T-cell subsets
like Th17 cells and follicular helper T cells as well as immunosuppressive cells like Foxp3 regulatory T cells. Foxp3 regulatory
T cells are well-known immunosuppressive cells. These cells inhibit the anticancer immune response and induce immunosuppression in many cancer types (4). In contrast, the infiltration of
de Me
decine, Universite
de
INSERM, U866, Dijon, France. 2Faculte
Bourgogne, Dijon, France. 3Centre Georges François Leclerc, Dijon,
France.
1
Corresponding Author: François Ghiringhelli, Centre Georges Francois Leclerc, 1
rue du professeur marion, Dijon 21000, France. Phone: 33-3-8039-3353;
Fax: 33-3-8039-3434; E-mail: fghiringhelli@cgfl.fr
doi: 10.1158/0008-5472.CAN-14-2748
2014 American Association for Cancer Research.
475–9. 2014 AACR.
The Biology of Th9 Cells
Generation of Th9 cells
IL9 was initially categorized as a Th2 cytokine. In 2008, a new
Th subset that preferentially produces IL9 and appears to be
distinct from Th2 cells was reported. These cells are generated
from mouse na€ve T cells after stimulation with TGFb and IL4 in
the presence of TCR signaling and costimulation (9, 10). However, IL9 is not specific to Th9 cells and could be secreted in smaller
amounts by Treg, Th17, or Th2 cells. During Th9 differentiation,
these cells discontinue expressing the Th2 cytokines, IL4, IL5, and
IL13, while initiating transcription of IL9 (13). Many cytokines are
known to affect Th9 differentiation. Clearly Th1-related cytokines
like IFNg and IL27 inhibit IL9 production and Th9 differentiation
(16). In contrast, some Th17-related cytokines like IL21 and IL23
inhibit Th9 cell polarization probably via their capacity to induce
STAT3 activation (13, 17). Similarly, some cytokines related to
type 2 immunity like IL2, IL10, and IL25 promote IL9 production
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475
Published OnlineFirst January 14, 2015; DOI: 10.1158/0008-5472.CAN-14-2748
gran et al.
Ve
and Th9 differentiation (12, 18). In addition, cytokine costimulation could play a role in Th9 differentiation. The Notch1/Jagged2
pathway is required for optimal Th9 polarization (19). Finally,
OX40 stimulation by OX40L expression on antigen-presenting
cells seems to be a key costimulation involved in the specific
induction of Th9 polarization (20).
Transcriptional program of Th9 cells
Though the transcriptional program of Th9 cells is not yet
described completely, some transcription factors have been
shown to be essential for Th9 polarization. These include STAT6,
GATA3, PU.1, and IRF4. It is noteworthy that the transcription
factors STAT6 and GATA3 are not expressed exclusively during
Th9 cell differentiation, but are also expressed in Th2 cells. STAT6
is phosphorylated during Th9 differentiation because of the
engagement of IL4R signaling, and is indispensable for Th9
differentiation. GATA3, whose expression is induced by phosphorylated STAT6, is also required for Th9 differentiation. Accordingly, the generation of Th9 cells was absent in STAT6-deficient
and GATA3-deficient mice, which confirmed that STAT6 and
GATA3 were essential in the generation of Th9 cells (9). However,
some data demonstrate that GATA3 is not directly involved in the
transcriptional regulation of the il9 gene, but acts rather as a
molecule involved in the downregulation of Foxp3, a protein that
could negatively affect Th9 development (21).
On the other hand, TGFb is also required for Th9 differentiation, but only a small fraction of Th9 cells express Foxp3, suggesting that Foxp3 is not essential for Th9 lineage commitment.
Moreover, the ectopic expression of Foxp3 reduces IL9 production
by Th9 cells (21), thus demonstrating a negative effect of Foxp3 on
Th9 differentiation. TGFb induces the activation of the SMAD
pathway and the expression of PU.1, which could restrain Th2
polarization (22). In the absence of PU.1, Th9 polarization was
impaired, whereas PU.1 infection of Th2 cells decreased IL4
secretion and promoted Th9 polarization (22). PU.1 was shown
to bind to the il9 promoter and to induce the recruitment of the
histone acetyltransferases Gcn5 and PCAF, thus leading to permissive chromatin conformation of the il9 gene (23).
IRF4 is also required for Th9 differentiation, but this transcription factor is also essential for Th2 and Th17 cell differentiation.
IRF4 heterodimerizes with PU.1 or the AP1 transcriptional factor
BATF on DNA. Like in Th17 cells, IRF4 cooperates with BATF to
induce the transcriptional program of Th9 cells (24). It remains to
be determined whether IRF4-PU.1 heterodimers also have an
impact on the Th9 transcription program. IRF1 is a Th1 transcription factor that is expressed in Th9 cells upon stimulation with
IL1b. This factor binds directly on il9 and il21 promoters, and is
essential to boost production of both cytokines (15). This factor is
a powerful enhancer of the Th9 program. It remains to be
determined whether IRF1 acts alone or in combination with other
transcription factors involved in Th9 polarization.
In vivo presence of Th9 cells in physiopathologic contexts
Th9 cells have been observed in many inflammatory contexts in
both humans and mouse models. However, the presence of Th9
cells is mainly associated with type 2 immunity-related processes.
Th9 cells have been found in the peripheral blood of allergic and
asthmatic patients. In a population of atopic patients, a greater
production of IL9 was observed in CD4 T cells stimulated with
house dust mite extract or cat allergens (25). Similar results were
observed in murine models of an ovalbumin airway inflamma-
476 Cancer Res; 75(3) February 1, 2015
tion model in which Th9 cells could be detected in the draining
lymph nodes and in lung tissues (26). In this context, Th9 cells
seem to play a pathogenic role and induce mucus production and
infiltration of the airspace by mast cells and eosinophils in goblet
cell hyperplasia. In helminth parasite diseases, another type 2
immunity-related disease, Th9 are essential for parasite eradication (27).
In the context of cancer, the presence of Th9 cells has been
described in lung metastatic pleural effusion and in tumor-infiltrating lymphocytes of human melanoma (14, 28).
The Mechanism of the Antitumor Effects
of Th9
Three recent articles have shown the ability of Th9 cells to
control tumor growth. The seminal observation was made by
Purwar and colleagues (13) who inadvertently discovered their
role. They observed that RORgt-deficient mice showed reduced
tumor growth and presented a high number of IL9-producing
CD4 T cells, suggesting that IL9 could play a role in the protective
antitumor immunity observed in RORgt-deficient mice. To test
the role of IL9 in this model, they treated melanoma-bearing
RORgt-deficient mice with an IL9-neutralizing antibody, and
noted that IL9 depletion promoted melanoma growth. In addition, they found that the antitumor effect of adoptive transfer of
antigen-specific Th9 cells was greater than that of Th1 or Th17 cell
transfer in the B16 melanoma model. These results were confirmed by Lu and colleagues (14), who found that the adoptive
transfer of ovalbumin-specific Th9 cells had antitumor effects in
the setting of subcutaneous lung metastasis of ovalbuminB16F10. The underlying mechanism accounting for the anticancer
functions of Th9 cells remains ambiguous. Purwar and colleagues
(13) observed a peptide-specific and granzyme B–dependent
killing capability of these cells. In these two reports, it was
suggested that IL9 was involved in the anticancer effect of Th9
cells. IL9 could target the activation and proliferation of mast cells,
which could have cytotoxic functions against tumor cells. However, the role of mast cells on cancer growth remains controversial
and some report underline the proangiogenic and the immunosuppressive function of mast cells. In addition, mast-cell infiltration of human tumors is associated with a poor outcome in
cancers (29). IL9 could induce an antitumor immune response
through different mechanisms. Lu and colleagues (14) demonstrated that IL9 could activate epithelial lung cells to produce
CCL20, the ligand of CCR6. This chemokine attracts CCR6þ
dendritic cell (DC) into the tumor bed and favors tumor antigen
uptake and presentation. In addition, this chemokine also attracts
CCR6þ CD8 CTL into the tumor bed in which they could then
eradicate cancer cells. IL9 was also shown to enhance DC survival
and to enhance their ability to generate anticancer protective
immunity. In lymphoma, these antitumor effects are imbalanced
by the expression of IL9R on tumor cells. In this case, IL9 drives
STAT3 and STAT5 activation in tumor cells and directly promotes
survival and proliferation. As a consequence, high expression of
IL9 is associated with a poor prognosis (30).
More recently, we observed that IL1b is a determinant factor in
boosting Th9 polarization by enhancing IL9 and IL21 secretion
without skewing Th9 cell polarization. We demonstrated that
engagement of IL1 receptor induces the activation of the tyrosine
kinase Fyn via MyD88 adaptor. Fyn drives the phosphorylation of
the transcription factor STAT1, and its subsequent direct binding
Cancer Research
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Published OnlineFirst January 14, 2015; DOI: 10.1158/0008-5472.CAN-14-2748
Th9 Cells and Cancer
IL1β
IL1R
Figure 1.
IL1b enhances Th9 differentiation in an
IRF1-dependent manner. Classical Th9
differentiation in the presence of
TGFb and IL4 induces IRF4, PU.1, and
BATF transcription factors that
interact with il9 and il21 promoters to
activate their expression. In an IL1b
context, such as cancer, the
engagement of IL1 receptor induces
the activation of the tyrosine kinase
Fyn via MyD88 adaptor. Fyn drives the
phosphorylation of the transcription
factor STAT1 on the tyrosine 701
residue and its binding to the
promoter of the gene encoding IRF1.
IRF1 binds to the il9 and il21 promoters,
thus increasing the secretion of both
IL9 and IL21.
MyD88
p-STAT1
(S727)
Fyn
p-STAT1
(S727, Y701)
APC
IL4
irf1
IRF4, PU.1, BATF
TGFβ
IL9, IL10, IL21
PU.1
BATF
IRF4
IRF1
il9
PU.1
BATF
IRF4
IRF1
il21
TCR activation
© 2015 American Association for Cancer Research
to the promoter of the gene encoding IRF1. IRF1 is, thus, essential
for the transcription of both il9 and il21 by its capacity to bind to
both promoters. IRF1 was detected only when Th9 cells were
polarized in the presence of IL1b. IL1b does not globally affect the
early differentiation of Th9 cells, but enhances their function
through the IRF1-dependent increase in the production of IL9
and particularly IL21. Importantly, although IRF1 was identified
as a specific Th1 cell–associated transcription factor (31), upregulation of IRF1 expression in Th9 cells does not skew Th9
polarization to IFNg-producing cells (Fig. 1; ref. 15).
Interestingly, IL1b stimulation boosted the antitumor activity
of Th9 cells in different models of adoptive cellular therapy (15).
Th9 cells differentiated with IL1b exert antitumor effects in the
ovalbumin-B16F10 model, the ovalbumin-LLC model and in the
B16F10 model using TCR transgenic mice, which recognize tyrosinase-related protein 1 (TRP-1), a melanocyte differentiation
antigen expressed by B16F10. More importantly, IL1b-induced
Th9 cells are also effective in a model of spontaneous melanoma
that developed in mice expressing the human RET oncogene
under the control of the metallothionein promoter (MT/ret mice).
RET transgenic mice develop an uveal melanoma associated with
the rapid development of metastatic disease (32). In this model,
both classical and IL1b-induced Th9 cells had an antitumor effect
on primary ocular tumors, but only IL1b-induced Th9 cells
inhibited the onset of metastasis.
Conventional Th9 cells produce large amounts of IL9 and small
amounts of IL21, and their anticancer effects are dependent on
IL9. In contrast, for Th9 cells differentiated in the presence of IL1b,
IL9 blockade has a minor effect on their anticancer properties. In
addition, in our model, Th9 cells did not feature expert killing
functions and mast cells were not involved in their anticancer
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effect. Instead, Th9 cells differentiated in the presence of IL1b
produced high levels of IL21 and exerted IL21-dependent anticancer effects. IL21 is a cytokine, which is classically produced by
activated CD4 T cells. This cytokine is a well-known stimulator of
IFNg production and enhances the cytolytic activity of NK cells
and CD8 T cells. In particular, IL21 boosts the ability of IL2 and
IL15 to activate NK cells' cytolytic and secreting function, augments IL15-induced proliferation of murine CD8 T cells, and
promotes clonal expansion of antigen-stimulated human CD8 T
cells (33, 34). In line with this, we observed that IL21 derived from
Th9 cells induced IFNg production by NK and CD8 cells. This
IFNg produced by host NK and CD8 T cells was required for the
anticancer effects of Th9 cells (Fig. 2). In humans, recombinant
IL21 was tested in a multicenter phase II study of patients with
metastatic melanoma. This treatment gave interesting stigmata of
efficacy with an overall response rate of about 25% in the first-line
treatment of metastatic melanoma (35). In this respect, because
IL1b-induced Th9 cells are able to secrete copious amounts of
IL21, they could represent an attractive candidate for a clinical
evaluation of anticancer cell therapy. The advantage of cell therapy rather than recombinant cytokine therapy could be the
specific homing of transfer T cells to the tumor bed, which could
induce a higher level of cytokines at the tumor site than is the case
with systemic injections.
Future Direction and Concluding Remarks
Recent clinical trials using checkpoint inhibitors like antiCTLA4 and anti-PD1/PDL1 underline the efficacy of redirecting
endogenous anticancer immunity to fight cancer. In addition,
cellular therapy with CD8 or CD4 T cells based on the transfer of
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477
Published OnlineFirst January 14, 2015; DOI: 10.1158/0008-5472.CAN-14-2748
gran et al.
Ve
IL9-dependent effects
IL21-dependent effects
NK
Mast cells
Cytolytic
functions
Cytotoxic
capacity
CCR6+ DC
CCR6+ CD8
recruitment
IFNγ
secretion
CCL20
Th9
CD8
Proliferation
Increased
survival
DC
Granzyme B
IFNγ
secretion
Figure 2.
Antitumor activity of Th9 cells. Th9
cells have anticancer properties via
granzyme B release. On the other
hand, IL9 can increase the cytotoxic
capacity of mast cells and DC survival.
IL9 also activates epithelial lung cells
to produce CCL20, which attracts
þ
þ
CCR6 DC and CCR6 CD8 into the
tumor bed. IL21-dependent effects
occur through CD8 proliferation and
increases in NK cytolytic functions.
IL21 derived from Th9 cells induces
IFNg production by NK and CD8 cells.
Killing
capacity
© 2015 American Association for Cancer Research
tumor-specific lymphocyte populations expanded in vitro also
demonstrated some efficacy in many trials. This strategy, however,
is currently based on the addition of empirical clinical trials, and
will probably benefit from better understanding of the particular
conditions needed to induce more potent and longer-lasting
antitumor responses.
Recent studies on Th9 cells, which showed the ability of Th9
cells and especially Th9 cells differentiated in the presence of IL1b
to induce major antitumor effects in different models, underscore
the potential relevance of this subset for future clinical trials of
adoptive cell therapies. These cells seem to be the ideal candidate
because in contrast with other helper cells, their IL9 expression
will induce the recruitment of bystander killer cells like NK cells
and CD8 T cells with the CCL20/CCR6 axis. IL9 will also promote
antigen presentation and CD8 priming (13, 14). Nevertheless,
one of the major problems of adoptive transfer is the poor stability
of helper T cell subsets once transferred in vivo. For example, it has
been suggested that CD4 T cells differentiated into Th17 cells are
better anticancer cells in the setting of established melanoma
tumors than are IFNg-secreting Th1 cells. However, Th17 cells
convert into IFNg-producing cells after adoptive transfer, and
tumor rejection is mainly dependent on the secretion of IFNg
(36, 37). This transdifferentiation is not observed in the case of
Th9 cells differentiated in presence of IL1b. These cells conserved
their ability to produce IL9 and IL21 days after in vivo injection. In
addition, Th9 cells differentiated in presence of IL1b antitumor
activity are strictly dependent on IL21, and IFNg-deficient Th9
conserved their anticancer function. In contrast, Th9 cells differentiated without IL1b antitumor activity are dependent on IL9.
Together, these data provide a strong impetus to investigate the
anticancer efficacy of adoptive transfer of Th9 cells in patients with
melanoma cancer.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
The authors thank Philip Bastable for the editing of the article.
Received September 16, 2014; revised November 14, 2014; accepted
November 17, 2014; published OnlineFirst January 14, 2015.
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Cancer Res; 75(3) February 1, 2015
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479
Published OnlineFirst January 14, 2015; DOI: 10.1158/0008-5472.CAN-14-2748
Th9 Cells: A Novel CD4 T-cell Subset in the Immune War against
Cancer
Frédérique Végran, Lionel Apetoh and François Ghiringhelli
Cancer Res 2015;75:475-479. Published OnlineFirst January 14, 2015.
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